Recombinant human insulin became the first authorized biologic in 1982. Junod, Suzanne White. “Celebrating a milestone: FDA's approval of first genetically-engineered product.” Update (2007): 43-44. The biologics industry has expanded dramatically since then with the addition of numerous new biologics, providing much needed therapeutic options for numerous diseases from hemophilia to cancer. In 2015, the U.S. FDA approved thirteen new biologics, nine of which were classified as “first-in-class” therapeutics. FDA Center for Drug Evaluation and Research, “Novel Drugs 2015 Summary”, January 2016. <http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM481709.pdf>.
The great promise of biologics as therapeutics faces numerous pragmatic challenges, not the least of which is the cost and complexity of production. The regulatory framework is also necessarily different than traditional small molecule pharmaceuticals:
“Because, in many cases, there is limited ability to identify the identity of the clinically active component(s) of a complex biological product, such products are often defined by their manufacturing processes. Changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the product's safety, identity, purity and potency. Traditional drug products usually consist of pure chemical substances that are easily analyzed after manufacture. Since there is a significant difference in how biological products are made, the production is monitored by the agency from the early stages to make sure the final product turns out as expected.”
U.S. FDA, Frequently Asked Questions About Therapeutic Biological Products, <http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelope dandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm113522.htm>.
Production and supply of biologics is therefore a key practical bottleneck in the flow of biologics to patients in need. Prices for biologics are correspondingly high relative to traditional small molecule chemical drugs. As a result, cost benefit analysis of biologics becomes critical in making decisions regarding access. See, e.g., Joensuu, Jaana T., et al. “The cost-effectiveness of biologics for the treatment of rheumatoid arthritis: a systematic review.” PloS one 10.3 (2015): e0119683; Huoponen, Saara, and Marja Blom. “A Systematic Review of the Cost-Effectiveness of Biologics for the Treatment of Inflammatory Bowel Diseases.” PloS one 10.12 (2015): e0145087.
In an effort to incentivize additional supply and lower costs, The U.S. federal government enacted the Biologics Price Competition and Innovation Act of 2009 as part of the Patient Protection and Affordable Care Act of 2010. This new law established the legal pathway and mandate for “biosimilars” i.e. generic biologics to secure market authorization. Ahmed, Isiah, Ben Kaspar, and Uma Sharma. “Biosimilars: impact of biologic product life cycle and European experience on the regulatory trajectory in the United States.” Clinical therapeutics 34.2 (2012): 400-419. The European Medicines Agency has been at the global forefront of biosimilars regulation with the first biosimilar approvals. Ibid.
One means of improving supply and reducing cost would be improved productivity through cost effective measures to increase product yield from existing biologics manufacturing. Ideally this would be accomplished with minimal capital expense. And of course, the resultant product would have to survive a rigorous regulatory review and evaluation analogous to proposed biosimilars or “major” production process changes under FDA or other Medicines agencies' regulations (e.g. EMA).
Due to the intense commercial and healthcare pressures on biologics production and cost, the state of the art for biopharmaceutical production involves extensive, multifaceted optimization and manipulation of many parameters in creating and culturing cells for protein biomolecule production. Almo S C, Love J D. Better and faster: improvements and optimization for mammalian recombinant protein production. Current opinion in structural biology. 2014; 26:39-43. doi:10.1016/j.sbi.2014.03.006; Mammalian Cell Cultures for Biologics Manufacturing (2014) Advances in Biochemical Engineering/Biotechnology 139 (Zhou, W. and Kantardjieff, A. eds).
Many cell culture process manipulations are routinely used. Abu-Absi, Susan, et al. “Cell culture process operations for recombinant protein production.” Mammalian cell cultures for biologics manufacturing. Springer Berlin Heidelberg, 2013. 35-68. For example, culture parameters, chemical agents and genetic engineering approaches have all been applied to cause cell cycle inhibition to increase specific cellular productivity to boost protein biomolecule yields. Du, Zhimei, et al. “Use of a small molecule cell cycle inhibitor to control cell growth and improve specific productivity and product quality of recombinant proteins in CHO cell cultures.” Biotechnology and bioengineering 112.1 (2015): 141-155.
Despite the extensive and ongoing efforts to improve protein biomolecule production, there remains intense commercial pressure and medical need to find new ways for further improvement.